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DNA mutations 'hotspots' may help determine cancer risk, study says

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Mutation "hotspots" in DNA where risk for genetic mutations are significantly raised have been identified by researchers, which could lead to potentially better ways for determining cancer risks. Photo by geralt/pixabay

By Allen Cone, UPI

Researchers have identified mutation "hotspots" in DNA where genetic mutations are significantly raised, leading to potentially better cancer risk determination.

These mutations, defined as "typos" by researchers at Indiana University in Bloomington, occur when DNA replicates during cellular division. Their findings were published in two papers, one on replication errors and the other on substitution patterns, in the August issue of the journal Genetics.

[post_ads]"This research gets us closer to understanding how the cell's replication machinery interacts with DNA," Dr. Patricia Foster, a professor emerita in the IU Bloomington College of Arts and Sciences' Department of Biology, said in a press release. "If you can understand exactly why an error occurs at a particular point on the DNA in bacteria, it gets you closer to understanding the general principles."

These random mistakes in DNA play a large role in many cancer types, she said.

The specific "hotspots" identified deal with E. coli and related bacteria, but the researchers believe this research can provide a roadmap to finding similar trouble spots in human DNA.

The researchers found that the chances of DNA replication errors in E. coli were up to 18 times more likely in DNA sequences where the same chemical "letter" in the sequence repeats multiple times in a row. Also, the errors were up to 12 times more likely in DNA sequences with a specific three-letter pattern.

Because of the huge amount of data -- the bacteria's entire genome of 30,000 mutations accumulated during 250,000 generations -- the research provides the "statistical weight" required to pinpoint the error rates with high accuracy, the researchers wrote.

In DNA replication, there is a "proofreader" enzyme and a molecular pathway called mismatch repair. Both act as a defense against mistakes from the enzyme -- called DNA polymerase. The genome is copied at 1,000 letters per second.

In the proofreader function, the copying process occurred after detecting a mistake. The "switching off" of this function caused 4,000 times more errors. When the mismatch repair, a backup system for the proofreader, is switched off, it caused 200 times more errors.
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"When we switch off these backup systems, we start to see 'pure' errors -- the places where the polymerase is more likely to make a mistake without intervention from other processes," Foster said. "Until now, I don't think anyone could truly see the seriousness of these error hotspots in DNA."

DNA replication errors are highest in certain tissues, including prostate and bones. A higher rate of cellular renewal means more mistakes as the DNA is copied.

"There are parts of the genome that contain 'cancer drivers,' where changes in the DNA can allow tumor cells to proliferate," Foster said. "If you could know what sections of the DNA had a higher risk for mutation, you might be able to focus your analysis on these 'hotspots' to predict what will happen next."